1. Field of the Invention
This invention relates to certain trans-2-substituted-5-aryl-2,3,4,4a5,9b-hexahydro-1H-pyrido[4,3-b]indole derivatives, their use as tranquilizing agents, pharmaceutical compositions thereof, a process and intermediates for their production.
2. Description of the Prior Art
Following the introduction of reserpine and chlorpromazine in psychotherapeutic medicine in the early 1950's, great effort has been expended in the search for other tranquilizing agents having improved biological profiles, several of which are .gamma.-carboline derivatives, also known in the art as derivatives of pyrido[4,3-b]indole.
In U.S. Pat. No. 3,687,961 8-fluoro-2-[3-(4-fluorophenylanilino)propyl]-1,2,3,4-tetrahydro-.gamma.-ca rboline was disclosed as a useful tranquilizer for warm-blooded animals. In U.S. Pat. No. 3,755,584 structurally related compounds with fluorine in the 6- or 8-positions and a specific p-substituted phenylalkyl moiety at the 2-position were found to have similar activity.
U.S. Pat. No. 3,983,239 disclosed hexahydro-.gamma.-carbolines of the formula ##STR4## where R.sup.1 is methyl or ethyl and R.sup.2 is hydrogen, methyl or ethyl. The stereochemical relationship of the hydrogen atoms attached to the carbon atoms at the 4a and 9b positions is not mentioned in this reference. However, one would expect them to be in a cis relationship based on the method of formation of the hexahydro-.gamma.-carboline nucleus from a 1,2,3,4-tetrahydro-.gamma.-carboline precursor by catalytic hydrogenation in the presence of platinum, a method well known in the art to introduce hydrogen atoms in a cis-configuration to a carbon-carbon double bond. The compounds claimed are neuroleptic agents said to be useful in the treatment of schizophrenia.
U.S. Pat. No. 3,991,199 discloses hexahydropyrimido[4,3-b]indoles, useful as analgesics and sedatives, some of which are of interest as tranquilizers, some as mucle relaxants and many of them show hypotensive activity; the compounds disclosed are of the formula ##STR5## and their pharmaceutically suitable salts, where the hydrogens attached to the carbon atoms in the 4a and 9b positions are in trans relationship to each other and where: when Y.sup.a is --H, --Cl, --Br, --CH.sub.3, -tert-C.sub.4 H.sub.9 or --OCH.sub.3 ; and when Y.sup.a is --CF.sub.3, X.sup.a is --H; and R.sup.a is, inter alia, hydrogen, benzyl; benzyl ring-substituted with methyl, methoxy or chloro; phenethyl; 3-phenylpropyl; 3-phenylpropyl ring-substituted with chloro, bromo or methoxy.
Recently issued Belgian patent No. 845,368 (Derwent No. 00043Y) discloses 5-phenyl-hexahydro-.beta.-carbolines, optionally substituted at positions 2 and 4 by methyl or ethyl and at position 3 by alkyl having from 1 to 3 carbon atoms, allyl or propargyl. They are said to be useful as antidepressants.
Recent West German Offenlegungsschrift No. 2,631,836, Derwent No. 09738Y, discloses structurally related octahydropyrido[4',3':2,3]indolo[1,7-ab][1]benzazepines which may be depicted by the above formula but with an ethylenic bridge between the two benzene rings, Y.sup.a and X.sup.a are hydrogen and R.sup.a is --CH.sub.2 CH.sub.2 COCH.sub.3 or --CH.sub.2 CH.sub.2 COC.sub.6 H.sub.5. They are said to be useful as analgesics and tranquilizing agents.
U.S. Pat. No. 4,001,263 discloses 5-aryl-1,2,3,4-tetrahydro-.gamma.-carboline tranquilizers of the formula ##STR6## where X.sup.b and Z.sub.b may be hydrogen or fluoro and values of R.sup.b include many of the 2-substituents disclosed for the compounds of formula (I). It has now, unexpectedly, been found that the trans-2,3,4,4a,5,9b-hexahydro-1H-pyrido[4,3-b]indoles of the present invention have markedly superior tranquilizing activity when compared with the corresponding 1,2,3,4-tetrahydro-.gamma.-carbolines.